SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis
| Autor: | Charles Warden, Nymph Chan, Sheryl Phung, Yuanzhong Wang, Shiuan Chen, Rumana Rashid, Dujin Zhou |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Antineoplastic Agents Hormonal Estrogen receptor Down-Regulation Mice Nude Apoptosis Breast Neoplasms Protein Serine-Threonine Kinases Endoplasmic Reticulum Sarcoplasmic Reticulum Calcium-Transporting ATPases 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Animals Humans Aromatase Protein kinase A Regulation of gene expression Mice Inbred BALB C Multidisciplinary biology Kinase Aromatase Inhibitors Endoplasmic reticulum Estrogen Receptor alpha Endoplasmic Reticulum Stress Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic 030104 developmental biology PNAS Plus Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research biology.protein MCF-7 Cells Female Estrogen receptor alpha Signal Transduction |
| Popis: | Many estrogen receptor alpha (ERα)-positive breast cancers initially respond to aromatase inhibitors (AIs), but eventually acquire resistance. Here, we report that serum- and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ERα in breast cancer, sustains ERα signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function in AI-resistant cells. We have further found that EnR stress response down-regulates ERα expression through the protein kinase RNA-like EnR kinase (PERK) arm, and SGK3 retains ERα expression and signaling by preventing excessive EnR stress. Our study reveals regulation of ERα expression mediated by the EnR stress response and the feed-forward regulation between SGK3 and ERα in breast cancer. Given SGK3 inhibition reduces AI-resistant cell survival by eliciting excessive EnR stress and also depletes ERα expression/function, we propose SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer. |
| Databáze: | OpenAIRE |
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